Angiogenesis, which is defined as the outgrowth of nutritive vessels from locally preexisting ones, is primarily based on the outgrowth of locally present endothelial cells and implies a delicate balance where both stimulating and inhibitory factors can influence the outcome. The primary players starting the process are the vascular endothelial growth factors (VEGFs), which stimulate endothelial cell growth, although some other key factors such as fibroblast growth factors (FGFs), placental growth factors (PIGFs), platelet-derived growth factors (PDGFs) and angiopoietins must come into play for vessels to mature and not deteriorate. Two possibilities exist in terms of local delivery of the angiogenic proteins. One is the delivery of the protein in a slow-release formulation. Fibrin or alginate formulations have been implanted, sub-epicardially releasing FGF. Another approach to get a local delivery over a period of time is gene therapy by local delivery of the vector carrying the therapeutic gene or with the development of vectors that are taken up and expressed only in the organ of interest. A transient overexpression, desirable for the treatment of ischemic heart disease, can be achieved with adenoviral vectors or naked plasmid. With VEGF gene transfection, angiogenesis and reendothelialization were demonstrated in animal cardiac ischemia models showing proof of principle for cardiac therapy and paving the way for clinical trials. Currently, about 200 patients have been treated with intramyocardial VEGF gene therapy for peripheral occlusive artery disease or for myocardial ischemia. Reported adverse events have been few and no worsening of atherosclerosis following treatment has been observed.